tbuckley/cabot-search huggingface dataset:
Left-Sided Degenerative Valvular Heart Disease in Type 1 and Type 2 Diabetes
Authors: Araz Rawshani, Naveed Sattar, Darren K. McGuire, Oskar Wallström, Ulf Smith, Jan Borén, Göran Bergström, Elmir Omerovic, Annika Rosengren, Björn Eliasson, Deepak L. Bhatt, Aidin Rawshani
Journal: Circulation (2022)

Background: The role of diabetes in the development of valvular heart disease, and, in particular, the relation with risk factor control, has not been extensively studied. Methods: We included 715 143 patients with diabetes registered in the Swedish National Diabetes Register and compared them with 2 732 333 matched controls randomly selected from the general population. First, trends were analyzed with incidence rates and Cox regression, which was also used to assess diabetes as a risk factor compared with controls, and, second, separately in patients with diabetes according to the presence of 5 risk factors. Results: The incidence of valvular outcomes is increasing among patients with diabetes and the general population. In type 2 diabetes, systolic blood pressure, body mass index, and renal function were associated with valvular lesions. Hazard ratios for patients with type 2 diabetes who had nearly all risk factors within target ranges, compared with controls, were as follows: aortic stenosis 1.34 (95% CI, 1.31–1.38), aortic regurgitation 0.67 (95% CI, 0.64–0.70), mitral stenosis 1.95 (95% CI, 1.76–2.20), and mitral regurgitation 0.82 (95% CI, 0.79–0.85). Hazard ratios for patients with type 1 diabetes and nearly optimal risk factor control were as follows: aortic stenosis 2.01 (95% CI, 1.58–2.56), aortic regurgitation 0.63 (95% CI, 0.43–0.94), and mitral stenosis 3.47 (95% CI, 1.37–8.84). Excess risk in patients with type 2 diabetes for stenotic lesions showed hazard ratios for aortic stenosis 1.62 (95% CI, 1.59–1.65), mitral stenosis 2.28 (95% CI, 2.08–2.50), and excess risk in patients with type 1 diabetes showed hazard ratios of 2.59 (95% CI, 2.21–3.05) and 11.43 (95% CI, 6.18–21.15), respectively. Risk for aortic and mitral regurgitation was lower in type 2 diabetes: 0.81 (95% CI, 0.78–0.84) and 0.95 (95% CI, 0.92–0.98), respectively. Conclusions: Individuals with type 1 and 2 diabetes have greater risk for stenotic lesions, whereas risk for valvular regurgitation was lower in patients with type 2 diabetes. Patients with well-controlled cardiovascular risk factors continued to display higher risk for valvular stenosis, without a clear stepwise decrease in risk between various degrees of risk factor control.
Reimagining physical activity for children following the systemic disruptions from the COVID-19 pandemic in Australia
Authors: Leon Straker, Verity Booth, Verity Cleland, Sjaan Gomersall, David Lubans, Tim Olds, Lindsey Reece, Nicola Ridgers, Michalis Stylianou, Grant Tomkinson, Kylie Hesketh
Journal: British Journal of Sports Medicine (2022)
Hypoxia-inducible factors: cancer progression and clinical translation
Authors: Elizabeth E. Wicks, Gregg L. Semenza
Journal: Journal of Clinical Investigation (2022)

Hypoxia-inducible factors (HIFs) are master regulators of oxygen homeostasis that match O2 supply and demand for each of the 50 trillion cells in the adult human body. Cancer cells co-opt this homeostatic system to drive cancer progression. HIFs activate the transcription of thousands of genes that mediate angiogenesis, cancer stem cell specification, cell motility, epithelial-mesenchymal transition, extracellular matrix remodeling, glucose and lipid metabolism, immune evasion, invasion, and metastasis. In this Review, the mechanisms and consequences of HIF activation in cancer cells are presented. The current status and future prospects of small-molecule HIF inhibitors for use as cancer therapeutics are discussed.
A phase 1 dose-escalation/expansion clinical trial of mocetinostat in combination with vinorelbine in adolescents and young adults with refractory and/or recurrent rhabdomyosarcoma: Interim results.
Authors: Noah Federman, Jacquelyn Crane, Amanda M Gonzales, Rubi Arias, Munther Baroudi, Arun S. Singh
Journal: Journal of Clinical Oncology (2022)

11553 Background: Rhabdomyosarcoma(RMS) is the most common soft tissue sarcoma in children. Relapsed/refractory(R/R) RMS has a poor outcome and remains an area of unmet need. Histone deacetylase (HDAC) inhibitors have been shown to have activity in preclinical models of RMS. Mocetinostat (Mirati Pharmaceuticals) is an investigational oral HDAC inhibitor, that targets HDACs 1, 2, 3 and 11. Mocetinostat displayed high activity in in vitro RMS cell lines, RMS xenograft models and exerted synergistic activity in combination with vinorelbine. We report early interim results of the Phase 1 trial of mocetinostat with vinorelbine in R/R RMS. Methods: An investigator initiated Phase 1,open-label, dose escalation/expansion clinical trial. A modified intent to treat approach is used for efficacy analysis for a target accrual of 20 subjects in the dose expansion cohort. Subjects with R/R RMS were age ≥ 18 years old(yo) for the phase 1 dose escalation cohort and ≥12 yo for the phase 1 dose expansion. Mocetinostat 40mg, 70mg or 90mg was taken orally 3 times weekly with vinorelbine 25mg/m 2 IV on day 1,8, and 15 in 21 day cycles. Maximum tolerated dose of mocetinostat in the dose escalation phase was 40mg, which was selected for dose expansion. Subjects were treated until disease progression by RECIST 1.1 or unacceptable toxicity. Results: A total of 8(6 FOXO translocation(+), 1 (FOXO-), and 1 unknown) have been enrolled at time of submission. 5 in dose escalation cohort, and 3 in dose expansion. Median age was 19 yo(range 16-63), Median prior treatment regimens were 2(range 1-4). All patients had measurable metastatic disease. 6 of 8 subjects had prior exposure to vinorelbine in prior salvage chemotherapy or maintenance chemotherapy. As of 20JAN2022 safety cutoff, most common AEs (all grades) observed in 7 evaluable treated patients include neutropenia (n = 5), anemia(n = 5), and nausea(n = 4). The only grade 3 or 4 treatment related AEs were neutropenia, lymphopenia and anemia. Myelosuppression was transient, reversible and responsive to growth factors. No SAEs related to mocetinostat and/or vinorelbine have been reported. As of efficacy cutoff 20JAN2022, 7 of 8 patients are evaluable for response. 4 subjects had a partial response (PR), 2 subjects had stable disease (SD) and 1 subject had progressive disease for a clinical benefit rate of 86% (CR+PR+SD). Rapid responses were seen in the majority of patients at median of 1.5 months(mos). Of the 6 responders, 4 had duration of responses (DOR) &gt; 6 mo with a median DOR of 8 mos (range 4-16mo). Conclusions: In this interim analysis, Mocetinostat plus vinorelbine shows high efficacy and acceptable safety profile in this heavily pretreated group of R/R RMS patients. This study is open to accrual and enrollment is ongoing. Clinical trial information: NCT04299113.
Universal genetic testing versus guideline-directed testing for hereditary cancer syndromes among traditionally underrepresented patients in a community oncology program.
Authors: Jeremy Clifton Jones, Tucker Coston, Katie Kunze, Michael A. Golafshar, Rohit Rao, Ewa Maria Wysokinska, Elizabeth Johnson, Edward D. Esplin, Robert Luke Nussbaum, Brandie Heald, Margaret Klint, Kathleen Barrus, Tanios S. Bekaii-Saab, Roxana Stefania Dronca, Jewel Samadder
Journal: Journal of Clinical Oncology (2022)

10588 Background: Detection of pathogenic germline variants (PGVs) has implications for cancer screening, prognostication, treatment selection, clinical trial enrollment and family testing. Published guidelines provide indications for PGV testing, determined by clinical and demographic factors, but these leave a significant number of cases missed by guideline-directed testing (incremental PGV). We have previously shown that 50% of patients with PVGs would not have been detected with guideline-based testing alone. In this project, we aimed to determine the feasibility and generalizability of this approach within a more racially/ethnically diverse cohort from a community cancer practice. Methods: We completed a prospective study of proactive germline genetic sequencing among patients with solid tumor malignancies at a community-based oncology practice in downtown Jacksonville, FL between June 2020, and September 2021. The patients were unselected for cancer type, stage, family history, race/ethnicity, and age. PGVs identified using an 84-gene NGS platform were stratified by penetrance. National Comprehensive Cancer Networks (NCCN) guidelines were used to determine incremental PGV rates. Results: 221 patients were enrolled, median age 63.0 years, 21.7% male. 56.6% of patients were white (non-Hispanic), 32.6% were black/African American, 5.4% were Hispanic. 39.8% of patients were commercially insured, 52.4% insured by Medicare/Medicaid and 2.7% uninsured. The cohort was comprised predominantly of breast cancer (61.5%), lung cancer (10.4%) and colon cancer (7.2%) patients. A total of 27 PGVs were identified in 23 patients. We found no significant difference in the rate of PGVs based on race/ethnicity. The overall rate of variants of uncertain significance (VUS) was numerically higher in black/African American patients (61.1%) compared with other ancestry (45%). 13 of 23 (56.5%) patients with detected PGVs did not meet NCCN guidelines for germline genetic screening (incremental PGVs). Conclusions: This prospective study found that universal multi-gene panel testing among patients from a racially/ethnically diverse cohort from a community cancer practice was associated with an increased detection of heritable variants with treatment implications over the predicted yield of targeted testing based on guidelines. This study is the first to evaluate this approach in an exclusively community-based practice. Clinical trial information: NCT04456140.
Frequency of loco-regional complications and their IMPACT on hospitalization outcomes in patients with pancreatic cancer.
Authors: Mihir Shah, Dennis Danso Kumi, Vaishali Deenadayalan, Kriti Ahuja, Elias Abate, Aakash Goyal, Shweta Gupta
Journal: Journal of Clinical Oncology (2022)

e16278 Background: Despite advances in medicine, pancreatic cancer continues to have a grim prognosis. It is not well studied if certain loco-regional complications pose higher prognostic risk than others and thus may be useful in estimating longevity and targeting care. Methods: National Inpatient Sample (NIS) was queried to identify adult patients with underlying pancreatic cancer between 2016-2018. Relative frequency and diagnosis of locoregional complications as principal diagnosis in these patients were identified and top 5 loco-regional complications were studied and compared for all-cause mortality, mean length of stay (LOS), mean total hospital charges (THC). Statistics were performed using the t-test, univariate and multinomial logistic regression. Results: There were 112,230 adult hospitalizations for pancreatic cancer. Top 5 loco-regional complications were cancer pain (8.6%), upper GI bleeding (UGIB) (8.4%), gastroduodenal obstruction (5.7%), failure to thrive (5%) and acute liver failure (2.8%). Mortality rate of all pancreatic cancer admissions was 7% and all loco-regional complications studied were associated with significant increased odds of mortality, the highest in patients with acute liver failure (AOR- 5.33, p &lt; 0.001). All Loco-regional complications studied were associated with statistically significant increased LOS with the highest among patients admitted with UGIB (p &lt; 0.001). UGIB was also associated with the highest THC whiles cancer pain admissions had a lower charge (p &lt; 0.001). Conclusions: Among Loco-regional complications in pancreatic cancer that were studied, cancer associated pain was the most frequent while acute liver failure was the most fatal (5x higher odds of mortality). UGIB was associated with the longest hospital LOS (6 more days) and the highest THC (over $100,000 extra per admission) whereas cancer associated pain was associated with the shortest length of stay and lowest total charge. Further efforts are needed to improve outpatient pain management in pancreatic cancer patients to prevent these admissions.[Table: see text]
Glycoproteomics as a powerful liquid biopsy-based predictor of checkpoint inhibitor treatment benefit in metastatic malignant melanoma.
Authors: Klaus Lindpaintner, Alan Mitchell, Chad Pickering, Gege Xu, Kimberly Vigal, Bianca Axenfeld, Rachel Rice, Xin Cong, Dennie T. Frederick, William Michaud, Genevieve Marie Boland, Danie Serie
Journal: Journal of Clinical Oncology (2022)

9545 Background: Protein glycosylation is the most abundant and complex form of post-translational protein modification. Glycosylation profoundly affects protein structure, conformation, and function. The elucidation of the potential role of differential protein glycosylation as biomarkers has so far been limited by the technical complexity of generating and interpreting this information. We have recently established a novel, powerful platform that combines liquid chromatography/mass spectrometry with a proprietary artificial-intelligence-based data processing engine that allows, for the first time highly scalable interrogation of the glycoproteome. Methods: Using this platform, we interrogated 526 glycopeptide (GP) signatures derived from 75 serum proteins in pretreatment blood samples from a cohort of 205 individuals (66 females, 139 males, age range 24 to 97 years) with metastatic malignant melanoma treated either with nivolumab plus ipilimumab (95 patients) or pembrolizumab (110 patients) immune-checkpoint inhibitor (ICI) therapy. Results: In an optimized assay containing 27 glycopeptides and 20 non-glycosylated peptides, we identified 14 GPs with abundance differences at FDR q≤0.05 with regard to PFS. Using 40% of the cohort as a training set and selecting 12 glycopeptide and non-glycosylated peptide biomarker features of the 47 total by LASSO shrinkage, we created a multivariable-model-based classifier for PFS that yielded a hazard ratio (HR) for prediction of likely ICI benefit of 7.5 at p &lt; 0.0001. This classifier was validated in the test set comprised of the held-out 60% of patients, yielding a HR of 4.7 at a similar p-value for separating patients likely benefiting from ICI therapy and those likely not benefiting from ICI therapy (50% PFS of 18 months vs. 3 months based on classifier score above/below cutoff). This classifier has a sensitivity of &gt; 99% to predict likely ICI benefit, while still performing at a specificity of 26%, thus helping to safely reduce ultimately unnecessary and non-beneficial exposure to these agents of one in four who otherwise would unnecessarily be exposed to them. Conclusions: Our results indicate that glycoproteomics holds a strong promise as a predictor for checkpoint inhibitor treatment benefit that appears to significantly outperform other currently pursued biomarker approaches in this context.
Effect of phytate on hypercalciuria secondary to bone resorption in patients with urinary stones
Authors: J. Guimera Garcia, A. Martinez Moreno, M. Peraire Lores, P. Sanchis Cortes, J.L. Bauza Quetglas, E. Pieras Ayala, F. Grases Freixedas
Journal: European Urology (2022)
Lipid-Poor Renal Angiomyolipoma Mimicking Renal Cell Carcinoma on 68Ga-FAPI-04 PET/CT
Authors: Aisheng Dong, Qing Yang, Meimian Hua, Chao Cheng, Changjing Zuo
Journal: Clinical Nuclear Medicine (2022)

FAPI PET/CT findings of renal tumors have been rarely reported. We describe 68 Ga-FAPI-04 PET/CT findings in 1 case with lipid-poor renal angiomyolipoma and 1 case with high-grade clear cell renal cell carcinoma. Both tumors showed intense 68 Ga-FAPI-04 uptake. These 2 cases indicate that lipid-poor renal angiomyolipoma should be included in the differential diagnosis of FAPI-avid renal tumors.
OTHR-25 Germline Mutations in Pediatric Brain Tumor
Authors: Shaoqun Li, Mingyao Lai, Linbo Cai
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: The exploration of germline mutations in pediatric brain tumor is helpful to improve the understanding of tumor genesis, guide the treatment, and provide genetic counseling for patients and their families. METHODS: In this study, children with primary brain tumor aged ≤18 years old in Guangdong Sanjiu Brain Hospital were enrolled．Tumor tissue or cerebrospinal fluid (CSF) next-generation sequencing (NGS) tests were required for all included patients. The genetic mutations in these children were analyzed and patients with germline mutations were screened. RESULTS: 135 pediatric patients with NGS detection were included in this patients. 63 patients were medulloblastoma, 54 were glioma. The rest were 5 ependymoma, 2other embryonal tumors, 2 pineoblastoma, 2 germ cell tumors, 1 pituitary adenoma, 1 neuroepithelial tumor, 1 Schwannoma, 1 neuronal tumor, 1 craniopharyngioma and 1 Rosai-Dorfman disease. NGS was performed on tissues of 122 patients and CSF of 13 patients. 7 patients underwent whole exome sequencing and the remaining 115 patients underwent panel detection. 6.67% (9/135) patients took germline mutations, which included 4 gliomas, 3 medulloblastomas, 1 schwannoma and 1 ependymoma. The rate of germline mutations were 7.41% (4/54) and 4.76% (3/63) in gliomas and medulloblastoma, respectively. The germinal mutations included TP53 missense mutation, BLM nonsense mutation, MSH2 nonsense mutation, MSH2 frameshift mutation, SUFU frameshift mutation, FANCI frameshift mutation, SBDS splicing site mutation, NF2 nonsense mutation and DIS3L2 nonsense mutation. These mutations are closely related to with Ligemeni syndrome, Bloom syndrome, Lynch syndrome, nevus basal cell carcinoma syndrome, Fanconi anemia, Shwachman-Diamond syndrome, neurofibromatosis type II and Perlman syndrome, respectively. 2 glioma patients had a family history of cancer. CONCLUSION: Pediatric patients with glioma, medulloblastoma, schwannoma and ependymoma are easily harboring germline mutations. For these patients, a detailed genetic history of family members is required and genetic counseling is recommended.
Real-world treatment patterns and outcomes among patients (pts) with second-line (2L) and third-line (3L) metastatic triple-negative breast cancer (mTNBC) in England using the Cancer Analysis System (CAS).
Authors: Lawrence Chang, Peter S. Hall, Luciana Preger, Nikoleta Sjekloca, Estevan Bergamaco, Anne Broe, Plamena Petrova, Paul Berg, Adam Reich, Neha Pawar, Mahdi Gharaibeh
Journal: Journal of Clinical Oncology (2022)

1075 Background: TNBC is the most aggressive type of breast cancer due to rapid growth, metastasis, and recurrence post-treatment. This study aimed to assess real-world treatment patterns and survival of pts with mTNBC who received 2L and 3L therapy in England and report OS and PFS of pts receiving 2L therapies stratified by treatment-free interval from the curative setting. Methods: This retrospective study using the CAS database, included pts with mTNBC who received at least three systemic treatments (at least two in metastatic setting) for TNBC during the years 2012 to 2020. Cohort 2L included pts with initial early-stage BC diagnosis and treatment (at least two systemic treatments prior to 2L). Cohort 3L included pts initially diagnosed with either early-stage TNBC, or de novo advanced TNBC (at least two systemic treatments prior to 3L). The two cohorts are not mutually exclusive. The study outcomes were stratified by cohort (Cohort 2L and Cohort 3L ) and treatment-free interval (&lt;12 m versus ≥12 m from end of curative treatment to start of 1L treatment, Cohort 2L only). Kaplan-Meier methods estimated progression-free survival (PFS) and overall survival (OS). PFS was proxied by ‘Time to treatment discontinuation or death’ (TTDD). Log-rank tests compared the distribution of OS and PFS for 2L stratified by treatment-free interval (&lt;12 m versus ≥12 m). Results: Cohort 2L included 606 pts and Cohort 3L included 374 pts. Tumor morphology was similar across Cohorts. Pts at 3L had worse ECOG performance score compared to 2L, and more pts with de novo advanced TNBC had brain metastasis at any point after diagnosis than pts diagnosed with early-stage TNBC. Regimens at 2L for Cohort 2L included capecitabine (32%), eribulin (16%), carboplatin and gemcitabine in combination (12%), and paclitaxel (10%). A similar distribution was seen for Cohort 3L . Regimens at 3L (Cohort 3L only), included eribulin (38%), capecitabine (16%), and paclitaxel (13%). Stratifying Cohort 2L by treatment-free interval did not exhibit significant differences in PFS nor OS by log rank tests (Table). Conclusions: This nationwide study, in England, accentuates the significant unmet need in 2L and 3L therapy for mTNBC highlighted by the poor prognosis. The stratification by prior treatment-free interval from curative setting did not show a difference in OS or PFS for patients receiving 2L treatment. [Table: see text]
Cancer cachexia impact on chemotherapy dose reduction, treatment discontinuation, and survival: A qualitative systematic review.
Authors: Philip D. Bonomi, Declan Walsh, David C. Currow, Gianluca Ballinari, Richard J. E. Skipworth
Journal: Journal of Clinical Oncology (2022)

e24103 Background: Cachexia is a syndrome of muscle wasting, weight loss, and anorexia, that frequently affects patients with advanced cancer across all major areas of oncology (surgical, medical, radiation, and chemotherapy), contributing to poorer treatment outcomes, including survival. In this qualitative systematic literature review, we reviewed the recent literature to assess the impact of cancer cachexia on chemotherapy dose reduction, treatment discontinuation, and survival. Methods: A systematic search was conducted on PubMed and Embase on November 26th, 2021, using the following search terms, among others: “cancer”, “cachexia”, “sarcopenia”, “muscle loss”, “body weight loss”, “chemotherapy”, “drug dose reduction”, “survival”, “treatment withdrawal”, and “treatment interruption”. 1,559 entries published between 2018 and 2021 were identified, of which 175 were duplicates. Publications were screened for eligibility and only original research in peer-reviewed journals were considered eligible. Inclusion criteria included: chemotherapy-specific studies; studies reporting on cachexia, body weight, or body composition changes; and studies reporting data on survival, chemotherapy dose reduction or treatment discontinuation, or occurrence of toxicities which may lead to chemotherapy dose reduction or treatment discontinuation in these patients. All studies that did not analyze the impact of cachexia on these outcomes were excluded. Results: A total of 63 studies, comprising a total of 15,832 patients, were considered eligible and selected for further analysis. The majority of analyzed studies, comprising 14,493 patients, reported associations between cancer cachexia (or its characteristics, such as weight loss or muscle wasting) and chemotherapy dose reductions in 7% of the studies, treatment discontinuation in 20% of the studies, and increased toxicity in 25% of the reports. Cachexia parameters were associated with inferior survival in 90% of the studies. The types of cancer most commonly associated with this effect were pancreatic (31% of studies), foregut (gastric, esophageal, and others, 17%), and lung cancer (14%). Conclusions: More than 70% of studies identified in the literature were retrospective assessments of patient records, while the remaining were prospective observational and interventional studies. In this review, cancer cachexia parameters were associated with reduced treatment delivery and inferior survival in multiple types of advanced cancer. These observations could have important implications for clinical practice, as early detection and successful treatment of cachexia might provide better outcomes for cancer patients undergoing chemotherapy. Disclosure: This study was funded by Helsinn Healthcare SA. Contact: Gianluca.Ballinari@helsinn.com .